TY - JOUR
T1 - Nrf2 Deficiency Exacerbates Obesity-Induced Oxidative Stress, Neurovascular Dysfunction, Blood-Brain Barrier Disruption, Neuroinflammation, Amyloidogenic Gene Expression, and Cognitive Decline in Mice, Mimicking the Aging Phenotype
AU - Tarantini, Stefano
AU - Valcarcel-Ares, M. Noa
AU - Yabluchanskiy, Andriy
AU - Tucsek, Zsuzsanna
AU - Hertelendy, Peter
AU - Kiss, Tamas
AU - Gautam, Tripti
AU - Zhang, Xin A.
AU - Sonntag, William E.
AU - De Cabo, Rafael
AU - Farkas, Eszter
AU - Elliott, Michael H.
AU - Kinter, Michael T.
AU - Deak, Ferenc
AU - Ungvari, Zoltan
AU - Csiszar, Anna
N1 - Funding Information:
This work was supported by grants from the American Heart Association (S.T., M.N.V.-A., Z.T., Z.U., and A.C.), the Oklahoma Center for the Advancement of Science and Technology (to A.C., A.Y., F.D., and Z.U.), the National Center for Complementary and Alternative Medicine (R01-AT006526 to Z.U.), the National Institute on Aging (R01-AG047879; R01-AG055395; R01-AG038747; P30 AG050911), the National Institute of Neurological Disorders and Stroke (NINDS; R01-NS056218 to A.C.), the National Heart, Lung and Blood Institute (R01-HL132553), the Oklahoma Shared Clinical and Translational Resources (OSCTR) program funded by the National Institute of General Medical Sciences (GM104938, to A.Y., P20GM104934 to F.D.), the National Eye Institute (R01-EY019494, to M.H.E. and core grant P30-EY021725), the Oklahoma IDeA Network for Biomedical Research Excellence (to A.C. and F.D.), the Presbyterian Health Foundation (to Z.U., A.C., A.Y., and F.D.), the Research to Prevent Blindness foundation (to the Dean McGee Eye Institute), and the Intramural Research Program of NIH (to R.D.C.). The authors acknowledge the support from the NIA-funded Geroscience Training Program in Oklahoma (T32AG052363).
Publisher Copyright:
© The Author(s) 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.
PY - 2018/6/14
Y1 - 2018/6/14
N2 - Obesity has deleterious effects on cognitive function in the elderly adults. In mice, aging exacerbates obesity-induced oxidative stress, microvascular dysfunction, blood-brain barrier (BBB) disruption, and neuroinflammation, which compromise cognitive health. However, the specific mechanisms through which aging and obesity interact to remain elusive. Previously, we have shown that Nrf2 signaling plays a critical role in microvascular resilience to obesity and that aging is associated with progressive Nrf2 dysfunction, promoting microvascular impairment. To test the hypothesis that Nrf2 deficiency exacerbates cerebromicrovascular dysfunction induced by obesity Nrf2 +/+ and Nrf2 -/-, mice were fed an adipogenic high-fat diet (HFD). Nrf2 deficiency significantly exacerbated HFD-induced oxidative stress and cellular senescence, impairment of neurovascular coupling responses, BBB disruption, and microglia activation, mimicking the aging phenotype. Obesity in Nrf2 -/- mice elicited complex alterations in the amyloidogenic gene expression profile, including upregulation of amyloid precursor protein. Nrf2 deficiency and obesity additively reduced long-term potentiation in the CA1 area of the hippocampus. Collectively, Nrf2 dysfunction exacerbates the deleterious effects of obesity, compromising cerebromicrovascular and brain health by impairing neurovascular coupling mechanisms, BBB integrity and synaptic function and promoting neuroinflammation. These results support a possible role for age-related Nrf2 dysfunction in the pathogenesis of vascular cognitive impairment and Alzheimer's disease.
AB - Obesity has deleterious effects on cognitive function in the elderly adults. In mice, aging exacerbates obesity-induced oxidative stress, microvascular dysfunction, blood-brain barrier (BBB) disruption, and neuroinflammation, which compromise cognitive health. However, the specific mechanisms through which aging and obesity interact to remain elusive. Previously, we have shown that Nrf2 signaling plays a critical role in microvascular resilience to obesity and that aging is associated with progressive Nrf2 dysfunction, promoting microvascular impairment. To test the hypothesis that Nrf2 deficiency exacerbates cerebromicrovascular dysfunction induced by obesity Nrf2 +/+ and Nrf2 -/-, mice were fed an adipogenic high-fat diet (HFD). Nrf2 deficiency significantly exacerbated HFD-induced oxidative stress and cellular senescence, impairment of neurovascular coupling responses, BBB disruption, and microglia activation, mimicking the aging phenotype. Obesity in Nrf2 -/- mice elicited complex alterations in the amyloidogenic gene expression profile, including upregulation of amyloid precursor protein. Nrf2 deficiency and obesity additively reduced long-term potentiation in the CA1 area of the hippocampus. Collectively, Nrf2 dysfunction exacerbates the deleterious effects of obesity, compromising cerebromicrovascular and brain health by impairing neurovascular coupling mechanisms, BBB integrity and synaptic function and promoting neuroinflammation. These results support a possible role for age-related Nrf2 dysfunction in the pathogenesis of vascular cognitive impairment and Alzheimer's disease.
KW - Endothelial dysfunction
KW - Long-term potentiation
KW - Vascular cognitive impairment
KW - Vascular cognitive impairment
KW - Vascular contributions to cognitive impairment and dementia
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U2 - 10.1093/gerona/glx177
DO - 10.1093/gerona/glx177
M3 - Article
C2 - 29905772
AN - SCOPUS:85048814233
SN - 1079-5006
VL - 73
SP - 853
EP - 863
JO - Journals of Gerontology - Series A Biological Sciences and Medical Sciences
JF - Journals of Gerontology - Series A Biological Sciences and Medical Sciences
IS - 7
ER -
